New drug Amplimexon

AmpliMed has begun enrollment of patients in a phase Ib trial to evaluate its lead candidate, Amplimexon, as a stand-alone therapy in patients with multiple myeloma.

The patients being enrolled in the trial have disease which has begun to progress following at least two prior therapeutic campaigns, either conventional or experimental.

Cell-based studies have shown that Amplimexon induces programmed cell death (apoptosis) in certain myeloma cell lines and in fresh myeloma cells taken from patients.

According to the company, Amplimexon may have the potential to slow or prevent the progression of myeloma without causing further bone marrow damage in patients in whom prior therapy has already caused serious damage.

This clinical trial has been designed to determine the tolerance of escalating doses of Amplimexon in this patient population, and to provide guidance on dosing for future clinical studies in multiple myeloma patients. Once the maximum tolerated dose has been established, the study will continue as a phase II study.

Should the outcome prove positive, this may lead to the design of a randomized clinical trial to more rigorously evaluate the benefits of the drug in this patient population.

Amplimexon has a unique way of attacking cancer cells that appears to avoid serious bone marrow toxicity and drug resistance that limits the usefulness of other chemotherapies. According to AmpliMed, the dug appears to kill cancer cells by causing the disruption of mitochondria, the energy producing factories of the cancer cell, resulting in the leakage of toxic substances which kill cancer cells.

"While there are many new drugs under development to address earlier stages of multiple myeloma, the safety profile of Amplimexon coupled with its potency against myeloma cells in culture suggests that it may have particular value in patients with preexisting bone marrow damage, who have progressed despite prior treatment," said Robert Ashley, chairman, president and CEO of AmpliMed.

New drug Evoltra(TM) / Clofarabine

Bioenvision's Evoltra(TM) Data Selected for Oral Presentation at ASCO 2006 Annual Meeting
Bioenvision, Inc. (Nasdaq:BIVN - News) today announced that the Scientific Program Committee of the American Society of Clinical Oncology (ASCO) has selected Bioenvision's Evoltra(TM) (clofarabine) adult acute myeloid leukaemia (AML) data for oral presentation at its 2006 ASCO Annual Meeting.

The data, to be presented by Professor Alan Burnett, is titled "Clofarabine in previously untreated elderly (greater than 65 yrs) AML patients with an unfavorable cytogenetic profile who are considered unfit for standard intensive chemotherapy."

The ASCO Annual Meeting will take place June 2-6th, 2006 in Atlanta, GA. The meeting attracts approximately 30,000 attendees from all over the world.

"The oral presentation at ASCO is an ideal opportunity to present the next phase of Evoltra(TM)'s clinical development program and follows the recent approval of Evoltra(TM) by the EMeA for treatment of relapsed/refractory pediatric acute lymphoblastic leukaemia" stated Dr. Andrew Saunders, Bioenvision's Medical Director.

About Evoltra(TM) (clofarabine)

The CHMP have adopted a positive opinion for the use of Evoltra(TM) (clofarabine) in "the treatment of acute lymphoblastic leukemia (ALL) in pediatric patients who have relapsed or are refractory to at least two prior regimens and where there is no other treatment option anticipated to result in a durable response. Safety and efficacy have been assessed in studies of patients less than or equal to 21 years old at initial diagnosis."

Bioenvision is also developing Evoltra(TM) for the treatment of adult acute myeloid leukemia (AML) as first-line therapy. The Company has completed enrollment of its Phase II clinical trial for the treatment of adult AML in elderly patients unfit for intensive chemotherapy and expects to file a Marketing Authorization Application in mid-2006 for the Company's first label-extension for Evoltra(TM).

In addition, Evoltra(TM) is in clinical development for the treatment of myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin's lymphoma, multiple myeloma, solid tumors and as a preconditioning regimen for transplantation. Bioenvision is also conducting late-stage preclinical development of Evoltra(TM) for the treatment of psoriasis and is planning further worldwide development of Evoltra(TM) in autoimmune diseases.

Evoltra(TM) (clofarabine) is a next generation purine nucleoside analog. Bioenvision holds an exclusive worldwide license for clofarabine. Bioenvision granted an exclusive sublicense to Genzyme to co-develop clofarabine for cancer indications in the US and Canada. Genzyme is commercializing clofarabine for cancer indications in the US and Canada under the brand name Clolar®. Bioenvision holds an exclusive license in the US and Canada for all non-cancer indications. Bioenvision originally obtained clofarabine development and commercialization rights under patents held by Southern Research Institute.

Clofarabine has been granted orphan drug designation for the treatment of both ALL and AML in the U.S. and Europe. In Europe, the designation provides marketing exclusivity for 10 years following Marketing Authorization.

About Bioenvision

Bioenvision's primary focus is the acquisition, development, distribution and marketing of compounds and technologies for the treatment of cancer. Bioenvision has a broad pipeline of products for the treatment of cancer, including: Evoltra(TM) (in co-development with Genzyme Corporation), Modrenal® (for which Bioenvision has obtained regulatory approval for marketing in the United Kingdom for the treatment of post-menopausal breast cancer following relapse to initial hormone therapy), and other products. Bioenvision is also developing anti-infective technologies, including the OLIGON® technology, an advanced biomaterial that has been incorporated into various FDA approved medical devices. For more information on Bioenvision please visit our Web site at www.bioenvision.com.

Certain statements contained herein are "forward-looking" statements (as such term is defined in the Private Securities Litigation Reform Act of 1995). Because these statements include risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Specifically, factors that could cause actual results to differ materially from those expressed or implied by such forward-looking statements include, but are not limited to: risks associated with preclinical and clinical developments in the biopharmaceutical industry in general and in Bioenvision's compounds under development in particular; the potential failure of Bioenvision's compounds under development to prove safe and effective for treatment of disease; uncertainties inherent in the early stage of Bioenvision's compounds under development; failure to successfully implement or complete clinical trials; failure to receive marketing clearance from regulatory agencies for our compounds under development; acquisitions, divestitures, mergers, licenses or strategic initiatives that change Bioenvision's business, structure or projections; the development of competing products; uncertainties related to Bioenvision's dependence on third parties and partners; and those risks described in Bioenvision's filings with the SEC. Bioenvision disclaims any obligation to update these forward-looking statements.

MMRF Give till it hurts

The Multiple Myeloma Research Foundation (MMRF) announced today that it has received the "Best in America" Seal of Excellence from Independent Charities of America (ICA), a nonprofit association that represents America's best charities.

The ICA Seal of Excellence is awarded to charities that upon rigorous independent review have been able to certify, document, and demonstrate on an annual basis that they meet the highest standards of public accountability, program effectiveness and cost effectiveness. Of the one million charities operating in the United States today, it is estimated that fewer than 50,000 meet or exceed these standards, and, of those, fewer than 2,000 have been awarded the Seal of Excellence.

With this newest honor, the MMRF is now the only nonprofit organization that also is 4-star rated from Charity Navigator, A+ rated by the American Institute of Philanthropy, meets the Better Business Bureau's Wise Giving Alliance for Charitable Accountability, and is recognized by the National Cancer Institute (NCI) for meeting the NCI's stringent research review guidelines for funding research grants.

"The addition of the "Best in America" Seal of Excellence from ICA truly validates the MMRF's sound stewardship of donor funds and separates us from other nonprofit organizations," said Scott Santarella, Executive Director and Chief Administration Officer of the MMRF. "The MMRF is a one-in-a-million organization and we are proud to be recognized as one of this country's very best."

About the Multiple Myeloma Research Foundation

The Multiple Myeloma Research Foundation (MMRF) was established in 1998 as a 501(c)3 non-profit organization by twin sisters Karen Andrews and Kathy Giusti, a newly diagnosed multiple myeloma patient, with the unique mission of accelerating the search for a cure for multiple myeloma. As the world's number one funder of myeloma research, the MMRF has raised more than $55 million to fund more than 130 research grants at more than 70 research institutions around the globe. Currently, the MMRF is funding more than 30 new compounds and approaches -- in pre-clinical testing and Phase I, II and III clinical trials -- that show promise in treating patients at all stages of the disease. For more information about the MMRF, please visit http://www.multiplemyeloma.org.

IMF Robert A. Kyle Lifetime Achievement Award

Nearly a century ago, Dr. William Mayo set the standard for treatment of patients at Mayo Clinic with these words, "the needs of the patient are the only needs to be considered." In 2003, the IMF decided to bestow a Lifetime Achievement Award annually to a physician whose work against myeloma reflected the dedication and compassion inherent in Dr. Mayo's vow. The IMF chose to name this award for Robert A. Kyle, M.D., whose life and work give new meaning to these words.

In his more than 40 years at Mayo Clinic, Dr. Kyle has never wavered from his commitment to the needs of patients with multiple myeloma. He has devoted his life's work to them. He has gained recognition the world over as a pioneer and respected leader in the advancement of research, clinical treatment, and education about myeloma.

When Brian Novis began doing his research to learn more about his disease, he was looking for the finest doctor available to help him. When he heard about Dr. Robert A. Kyle at the Mayo Clinic, Brian didn't know at the time that Dr. Kyle was considered to be the "grandfather" of myeloma treatment.

When Brian Novis and Brian Durie decided to create an international foundation dedicated to helping others with myeloma, the first person they contacted was Dr. Kyle. With a simple phone call, Dr. Kyle agreed to collaborate with the two Brians. He became a founding member of the Board of Directors and chairman of the IMF Scientific Advisory Board, a position he still holds today.

Dr. Kyle is the most frequently requested speaker at the IMF Patient & Family Seminars around the world. Through the IMF, Dr. Kyle has made himself accessible to thousands of patients and their families as well as to IMF staffers. His guidance and encouragement are as important today as when the IMF first began.

When Dr. Kyle was first approached about receiving his own Robert A. Kyle Lifetime Achievement Award his response to Susie Novis was, "I'm not done yet." His humility, dedication, sense of humor, and truly caring and compassionate nature are among the many reasons for which the IMF named this award in his honor.

Source: http://myeloma.org/

Long-term complete remission in IgD-myeloma

Long-term complete remission in IgD multiple myeloma (MM) is rare. This case report describes a patient with a stage IIIB IgD-MM, who was treated with conventional melphalan and prednisone chemotherapy. The monoclonal protein disappeared after four cycles and therapy was discontinued after 14 cycles. Re-evaluation after a follow up of more than 8 years demonstrates a continuing complete remission suggesting a cure. This is remarkable, considering that several adverse prognostic factors were present. In addition a concise review on IgD-MM is given.

Eur J Haematol. 2006 Apr;76(4):339-41

Bemelmans RH, van Toorn DW, van Leeuwen L, Schaar CG.

Department of Internal Medicine, Gelre Hospitals, Apeldoorn, The Netherlands.

PMID: 16519706 [PubMed - in process]

Long-term complete remission in IgD-myeloma

Long-term complete remission in IgD multiple myeloma (MM) is rare. This case report describes a patient with a stage IIIB IgD-MM, who was treated with conventional melphalan and prednisone chemotherapy. The monoclonal protein disappeared after four cycles and therapy was discontinued after 14 cycles. Re-evaluation after a follow up of more than 8 years demonstrates a continuing complete remission suggesting a cure. This is remarkable, considering that several adverse prognostic factors were present. In addition a concise review on IgD-MM is given.

Eur J Haematol. 2006 Apr;76(4):339-41

Bemelmans RH, van Toorn DW, van Leeuwen L, Schaar CG.

Department of Internal Medicine, Gelre Hospitals, Apeldoorn, The Netherlands.

PMID: 16519706 [PubMed - in process]

Physician of the Year - Dr. Bart Barlogie

Castle Connolly Medical Ltd., which publishes the annual "America's Top Doctors" guide, has named Dr. Bart Barlogie, director of the Myeloma Institute for Research & Therapy at the University of Arkansas for Medical Sciences at Little Rock, as a National Physician of the Year.

Barlogie and two other physicians will receive the award for clinical excellence during a ceremony Wednesday evening at the Metropolitan Club in New York City. Honored with Barlogie are Dr. Marilyn Bull of Riley Children’s Hospital in Indianapolis and Dr. Michael J. Zinner of Brigham & Women’s Hospital and Harvard Medical School in Boston.

Physician of the year recipients were selected from nominations submitted by physicians profiled in "America's Top Doctors."

Barlogie is among the world’s experts in the diagnosis and treatment of multiple myeloma. UAMS said Barlogie's research has more than doubled the annual survival rate of a myeloma patient upon diagnosis from three years to more than seven years.

Dendritic cell undertstanding

Tumor evasion of the immune system: inhibiting p38 MAPK signaling restores the function of dendritic cells in multiple myeloma

Siqing Wang, Jing Yang, Jianfei Qian, Michele Wezeman, Larry W. Kwak, and Qing Yi

From the Department of Lymphoma and Myeloma, Division of Cancer Medicine, and the Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, TX.

Dendritic cells (DCs) from patients with cancer are functionally defective, but the molecular mechanisms underlying these defects are poorly understood. In this study, we used the murine 5TGM1 myeloma model to examine the effects and mechanisms of tumor-derived factors on the differentiation and function of DCs. Myeloma cells or tumor culture conditioning medium (TCCM) were shown to inhibit the differentiation and function of BM-derived DCs (BMDCs), as evidenced by the down-regulated expression of DC-related surface molecules, decreased IL-12, and compromised capacity of the cells to activate allospecific T cells. Moreover, TCCM-treated BMDCs were inferior to normal BMDCs at priming tumor-specific immune responses in vivo. Neutralizing antibodies against IL-6, IL-10, and TGF- partially abrogated the effects. TCCM treatment activated p38 mitogen-activated protein kinase (MAPK) and Janus kinase (JNK) but inhibited extracellular regulated kinase (ERK). Inhibiting p38 MAPK restored the phenotype, cytokine secretion, and function of TCCM-treated BMDCs. BMDCs from cultures with TCCM and p38 inhibitor was as efficacious as normal BMDCs at inducing tumor-specific antibody, type 1 T cell, and cytotoxic T lymphocyte (CTL) responses and at prolonging mouse survival. Thus, our results suggested that tumor-induced p38 MAPK activation and ERK inhibition in DCs may be a new mechanism for tumor evasion and that regulating these pathways during DC differentiation provides new strategies for generating potent DC vaccines for immunotherapy in patients with cancer. (Blood. 2006;107:2432-2439)

PET scans to diagnose Multiple Myeloma

FDG PET Reassures and Reveals High Risk Multiple Myeloma
11.5.02

Press Release from the Journal of Nuclear Medicine

Whole body FDG PET scans were able to identify previously undetected disease and also confirm that pre-cancerous conditions had not become active disease for 66 patients with multiple myeloma and related conditions studied by researchers from Cedars-Sinai Medical Center in Los Angeles California. Their findings were published in the November, 2002 issue of the Journal of Nuclear Medicine.

For sixteen patients with previously untreated active myeloma, the whole body scans identified those at high-risk, and provided important information on their disease’s status. One quarter of the patients had no evidence of disease on a routine skeletal bone scan, but showed up positive on the PET scan. Another patient’s disease was upgraded from Stage IA to Stage IIIA. For four of the 16 who were considered to have stage III disease, the PET scan revealed that the disease had spread outside the bone marrow, a finding which is linked to a poor prognosis for survival. Likewise for the 26 patients with relapsing disease, PET identified new diseases sites for 81% of those scanned, and for 23%, new non-marrow sites, with the same prognosis noted above.

The authors noted that PET may have particular value for both relapsed and active/untreated disease in patients with nonsecretory multiple myeloma. This version of the disease, which affects about 2% of those with multiple myeloma, can be particularly difficult to diagnose and stage early on because of the absence of the characteristic M-protein, and the fact that tumors are often less pronounced than the more common type. PET, which measures metabolic function, was able to identify disease [not visible through other means.]

According to the authors, for patients with conditions that may evolve into multiple myeloma, and who require frequent and detailed testing to monitor their condition, PET scans may be particularly useful and even potentially cost saving. The study included 14 cases of MGUS (monoclonal gammopathy of undetermined significance). This condition, in which there is excessive production of an antibody protein by abnormal plasma cells, evolves into multiple myeloma about 20% of the time. All had negative PET scans at their first evaluation. Only one of the patients scanned developed multiple myeloma, [All have had a second scan, and these confirmed the others had no active disease.]

The authors conclude that FDG PET can play an important complementary role, along with CT, MRI, and bone scans, in the diagnosis and staging of individuals with this disease, and that further studies will refine its best uses. MRI and CT, while able to identify lesions, have difficulty distinguishing between active disease and scare tissue, bone fractures or benign disease.

Whole-Body 18F-FDG PET Identifies High Risk Myeloma was written by Brian G.M. Durie, MD, Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Comprehensive Cancer Center and Alan D. Waxman, MD, Allesandro D’Agnolo, MD and Cindy M. Williams, BS, Division of Nuclear Medicine, Department of Imaging, Cedars-Sinai Medical Center, Los Angeles, California.

Source: http://myeloma.org/main.jsp?type=article&id=717

Kyphoplasty report

Functional outcomes of kyphoplasty for the treatment of osteoporotic and osteolytic vertebral compression fractures.

Khanna AJ, Reinhardt MK, Togawa D, Lieberman IH

Cleveland Clinic Spine Institute and Minimally Invasive Surgery Center, Cleveland Clinic Foundation, Cleveland, OH, USA, ehenze1@jhmi.edu.

INTRODUCTION: Vertebral body compression fractures secondary to osteoporosis or malignant osteolysis are an increasingly common problem. The primary purpose of our study was to assess functional outcomes of kyphoplasty for the treatment of osteoporotic and osteolytic vertebral compression fractures. Our secondary purpose was to compare such functional outcomes in patients with osteoporosis versus multiple myeloma.

METHODS: The 314 consecutive patients prospectively included in our study had progressive and painful compression fractures as a result of osteoporosis or multiple myeloma that were refractory to nonoperative modalities. Of those 314 patients, the 211 (67.2%) patients (155 with osteoporosis and 56 with multiple myeloma) who had complete preoperative and postoperative data formed our final study group. All patients tolerated the kyphoplasty procedure well (that is, there were no adverse events in terms of perioperative patient condition). Follow-up ranged from 1 to 235 weeks (mean 55.0 weeks).

RESULTS: The average Owestry Disability Index score decreased by 12.6 points (P<0.001) in the overall group, by 11.8 points (P<0.001) at short-term follow-up, and by 8.6 points (P<0.001) at long-term follow-up. All SF-36 sub-scores except for general health and role-emotional showed statistically significant improvement from baseline values at the same time points. There was no statistically significant difference with regard to functional outcome in the osteoporosis and multiple myeloma sub-groups. CONCLUSIONS: Kyphoplasty provided a safe and effective treatment for pain and disability in patients with verterbral compression fractures secondary to osteoporosis and multiple myeloma. In addition, we found no statistically significant difference with regard to functional outcome between patients with osteoporosis and multiple myeloma.

PMID: 16518574 [PubMed - as supplied by publisher]

Resveratrol: Drink up

Resveratrol induces apoptosis of human malignant B cells by activation of caspase-3 and p38 MAP kinase pathways.

Shimizu T, Nakazato T, Xian MJ, Sagawa M, Ikeda Y, Kizaki M

Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

Red wine polyphenol, trans-resveratrol (trans-3,4',5-trihydroxy stilbene), has potent chemopreventive effects against various tumors. In this study, we found for the first time that resveratrol rapidly induces S phase cell cycle arrest of human malignant B cells including myeloma cells in dose- and time-dependent manners, followed by S phase cell cycle arrest through ATM/Chk pathway. Resveratrol-induced apoptosis occurs in association with the activation of caspase-3 and the loss of mitochondrial transmembrane potentials. In addition, resveratrol induces the phosphorylation of p38 MAP kinase, and specific inhibition of p38 MAP kinase abolishes the resveratrol-induced apoptosis, indicating that activation of the p38 MAP kinase pathway is required for inducing apoptosis in malignant B cells. These results suggest that resveratrol may have potential as a novel therapeutic agent for the patients with B cell malignancies including multiple myeloma.

PMID: 16427027 [PubMed - in process]

Bendamustine/Prednisone vs. Melphalan/Prednisore

Treatment of Bendamustine and Prednisone in patients with newly diagnosed multiple myeloma results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with Melphalan and Prednisone-a randomized phase III study of the East German Study Group of Hematology and Oncology (OSHO).

Ponisch W, Mitrou PS, Merkle K, Herold M, Assmann M, Wilhelm G, Dachselt K, Richter P, Schirmer V, Schulze A, Subert R, Harksel B, Grobe N, Stelzer E, Schulze M, Bittrich A, Freund M, Pasold R, Friedrich T, Helbig W, Niederwieser D

Department of Hematology and Oncology, University of Leipzig, Johannisallee 32A, 04103, Leipzig, Germany, dietger@medizin.uni-leipzig.de.

Purpose: This randomized phase III study compared bendamustine and prednisone (BP) to standard melphalan and prednisone (MP) treatment in previously untreated patients with multiple Myeloma (MM). Patients and Methods: To be included, patients had to have histologically and cytologically proven stage II with progressive diseases or stage III MM. They were randomly assigned to receive BP (n=68) or MP (n=63). The primary endpoint was the time to treatment failure (TTF). Secondary endpoints included survival, remission rate, toxicity and quality of life. Results: The overall response rate was 75% in the BP and 70% in the MP group. A significantly higher number of patients treated with BP achieved a complete remission than did patients receiving MP (32 vs. 13%; P=0.007), and the maximum response was achieved more rapidly in patients treated with BP compared to those receiving MP (6.8 vs. 8.7 cycles; P<0.02). TTF and remission duration were significantly longer in the BP group. Patients receiving BP had higher QoL scores and reported pain less frequently than patients receiving MP. Conclusion: BP is superior to MP with respect to complete remission rate, TTF, cycles needed to achieve maximum remission and quality of life and should be considered the new standard in first-line treatment of MM patients not eligible for transplantation.

PMID: 16402269 [PubMed - in process]

Research: Immunotherapy on Multiple Myeloma

Adenoviral-mediated transfer of human wild-type p53, GM-CSF and B7-1 genes results in growth suppression and autologous anti-tumor cytotoxicity of multiple myeloma cells in vitro.

Ren SP, Wu CT, Huang WR, Lu ZZ, Jia XX, Wang L, Lao MF, Wang LS

Department of Experimental Hematology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, People's Republic of China.

We have previously demonstrated the suppressive effect of a recombinant adenovirus carrying human wild-type p53, granulocyte-macrophage colony-stimulating factor, and B7-1 genes (Ad-p53/GM-CSF/B7-1) on the growth of laryngeal cancer cells. In the present study, we evaluated the effects of an Ad-p53/GM-CSF/B7-1-modified myeloma cell vaccine strategy aimed to induce apoptosis and to augment the immunogenicity of MM cells. Both MM cell lines and purified primary myeloma cells were infected with Ad-p53/GM-CSF/B7-1. High expression levels of these three genes were confirmed separately by Western blot, enzyme-linked immunosorbent assay (ELISA), and flow cytometry. When wild-type p53, GM-CSF and B7-1 genes were introduced, the growth of MM cells was inhibited via enhanced apoptosis and the immunogenicity of tumor cells was augmented. The combinatorial effect of these three genes on inducing cytotoxic T lymphocytes (CTLs) was more evident than that of p53 individually or any combinations of two (p53 plus GM-CSF or p53 plus B7-1). Furthermore, significant proliferation of autologous peripheral blood lymphocytes (PBLs) and specific cytotoxicity against autologous primary MM cells were induced in vitro. These results suggest that myeloma cell vaccination co-transferred with p53, GM-CSF and B7-1 genes may be a promising immunotherapeutic approach against MM.

PMID: 16001164 [PubMed - in process]

IMF Revlimid Update: Where do we stand?

Revlimid Update: Where Do We Stand?
By Brian G.M. Durie, MD
2.21.06

Revlimid® (Lenalidomide) is an important new agent for the treatment of myeloma. It has shown great promise as both a single agent and in combination with dexamethasone and other drugs. With use of Revlimid there is much less risk of nerve toxicity than with thalidomide, which is one of the reasons patients have been eagerly awaiting access to it.

Celgene has opened the unique expanded access protocol (EAP) at over 80 centers across the United States. Through this program, patients with relapsing myeloma can have access to free Revlimid in a protocol that consists of Revlimid plus dexamethasone. To find out if there is an open trial site close to you, call the IMF at 800-452-CURE (2873) or Celgene at 888-423-5436 or www.revlimid.com.

For patients with newly diagnosed myeloma, Revlimid is available through two national trials involving ECOG (Eastern Cooperative Oncology Group) and SWOG (Southwest Oncology Group). A number of other trials are being planned and will be available in the coming months in various disease settings. Check the Myeloma Matrix and the Myeloma Minute for announcements as these trials open, or call the IMF hotline at the above number.

At the present time, access to commercially available Revlimid by prescription is more limited. The FDA has approved Revlimid for MDS, (Myelo Dysplastic Syndrome), a type of pre-leukemia. This means that use for myeloma patients is "off-label." For myeloma patients whose oncologists have recommended therapy with Revlimid, this presents problems. First, since Revlimid will probably not be approved specifically for myeloma until later in the year, it will not, generally speaking, be covered by insurance for myeloma patients. Second, and perhaps more importantly, the commercial Revlimid pricing is currently set for the much lower dose schedule used for MDS (5-10mg daily versus 25mg daily for myeloma), thus making the cost disproportionately and prohibitively high for myeloma patients at this time. With specific FDA approval for myeloma, there are indications that the pricing will be geared to the recommended myeloma dosing and schedule. This is a delicate point in that although myeloma patients need and want Revlimid right now, FDA approval is absolutely required to promote use for myeloma. The 25mg capsule that is provided free through EAP is not an appropriate dose for MDS. Thus the 25mg capsule is not currently available commercially! This complex scenario will be worked out in the coming months.

Many drug formularies of insurance companies offering Medicare Part D drug coverage currently do include Revlimid for MDS. Thus if you have not done so already, it is recommended that myeloma patients do some research and sign up for an insurance plan under Medicare Part D prior to the May 15^th 2006 deadline in anticipation of reimbursement for Revlimid through this mechanism. Many pharmacies, including Walgreens, will help you determine which insurers in your region include the drugs you need in their coverage formularies.

Stay tuned for future updates.

Source: http://myeloma.org/main.jsp?source=link&source_link_id=2081&type=article&tab_id=1&menu_id=0&id=1724

IMF: Revlimid Update

Update on Lenalidomide (CC-5013; Revlimid®)
By S. Vincent Rajkumar, MD
6.9.05

S. Vincent Rajkumar, MD
Associate Professor of Medicine
Mayo Clinic
Rochester, Minnesota

Over the last five years, numerous clinical trials have shown that thalidomide is effective in the treatment of multiple myeloma. In fact, thalidomide plus dexamethasone (Thal/Dex) has rapidly become one of the more commonly used regimens for the initial treatment of myeloma. Given this success, there has been intense research to develop a safer and more effective version of thalidomide. Lenalidomide (CC-5013; Revlimid®) is the first analog (close cousin) of thalidomide to enter clinical trials. It may prove to be more effective and safer than thalidomide. Like thalidomide, it is taken by mouth, as a capsule, and does not carry the type of side effects commonly associated with cancer chemotherapy like nausea, vomiting, and hair loss.

Initial studies with lenalidomide, as with most new drugs to treat cancer, were carried out in the laboratory on myeloma cells and in animal models of myeloma. In these studies, the drug was found to be several-fold more powerful than thalidomide. This led to several clinical trials in patients with multiple myeloma.

The first clinical trials were conducted to determine the correct dose of the drug and to establish its safety (Phase I trials). These trials were carried out at the University of Arkansas (Little Rock, AR) and the Dana-Farber Cancer Institute (Boston, MA). These studies showed that the maximum tolerated dose of lenalidomide was 25mg daily. Importantly, in both trials, patients with advanced multiple myeloma responded to the treatment. At least a 25% drop in the M protein (M spike; paraprotein level) was seen in 50-60% of the patients. These results were particularly impressive because most patients had failed other effective regimens, and some had already failed thalidomide.

With the success of these initial trials, a larger trial was conducted to more accurately determine the response rate with lenalidomide in patients with relapsed and refractory myeloma (Phase II trial). This trial was conducted jointly at the Dana-Farber Cancer Institute, Mayo Clinic (Rochester, MN), St. Vincent’s Hospital (New York, NY), and the H. Lee Moffitt Cancer Center (Tampa, FL). Of 101 patients treated, approximately 25% achieved a partial response to therapy which is a 50% or higher reduction in M protein level. Overall about 35% of patients had a drop in their M spike by at least 25%.

Lenalidomide Exceeds Expectations in Relapsed and Refractory MM The Independent Data Monitoring Committee (IDMC) responsible for overseeing two clinical trials of lenalidomide (CC-5013; Revlimid®) found a statistically significant improvement in time to disease progression – the primary endpoint of these Phase III trials – in patients receiving Revlimid plus dexamethasone compared to patients receiving dexamethasone alone. The trials have been unblinded many months earlier than originally projected. Celgene Corporation is allowing all patients in these studies to get Revlimid if they want to. Plans are under way to offer expanded access to Revlimid for patients with previously treated myeloma (subject to appropriate regulatory approval).

Lenalidomide was in the news recently when two large randomized studies showed that the combination of lenalidomide plus dexamethasone (Rev-Dex) is significantly more effective than dexamethasone alone. These studies are referred to as Phase III trials, in which patients were assigned to either of the two treatments being studied by a computer program similar to a coin toss. All patients had relapsed/refractory myeloma. Over 700 patients participated in these Phase III trials. The time from diagnosis to myeloma progression was much longer in patients receiving lenalidomide plus dexamethasone compared to dexamethasone alone. These results are very exciting and suggest that lenalidomide is a very active drug to treat multiple myeloma. These studies will hopefully lead to approval of the drug by the Food and Drug Administration when the final efficacy and safety data are reviewed.

As with thalidomide, the effectiveness of lenalidomide in patients at the relapsed and refractory stage has led to clinical trials in newly diagnosed myeloma, as first-line treatment. In a recent Mayo Clinic trial, over 80% of patients with newly diagnosed myeloma responded to the combination of lenalidomide plus dexamethasone (Rev-Dex). There were far fewer serious side effects compared to the Thal-Dex regimen. As a result, Rev-Dex promises to be one of the major treatment options when patients are first diagnosed with myeloma. Since lenalidomide is not commercially available, the Rev-Dex regimen is currently available to patients only as part of clinical trials. In the United States, two large trials are available to patients with newly diagnosed myeloma. These trials are coordinated by the Eastern Cooperative Oncology Group (ECOG) and the Southwest Oncology Group (SWOG), and are available through many centers nationwide. Please visit the IMF website at www.myeloma.org or call 800-452-CURE (2873) to learn more about clinical trial enrollment.

Lenalidomide is dispensed as capsules. The most common dosing used in multiple myeloma is 25 mg given orally daily on days 1-21 and repeated every 28 days (days 22-28 are rest days). Doses are then modified based on side effects. The main side effects are low blood counts. Unlike thalidomide, significant sedation, constipation, or neuropathy is not common with this drug. Although no birth defects have been reported with lenalidomide, stringent precautions to prevent pregnancy and to prevent pregnant woman from receiving this drug are required.

The mechanism by which lenalidomide works is not fully known. It belongs to a class of drugs called “immunomodulatory drugs” (or “ImiDs”). It is felt to work by boosting the immune system to help fight the cancer cells more effectively. Lenalidomide is also directly toxic to the myeloma cells and likely interferes with the blood supply that is needed for cancer cells to grow.

Lenalidomide is not commercially available, but will hopefully be approved in the near future. It is a very promising and effective addition to the treatment of myeloma. Besides trials in newly diagnosed myeloma discussed above, ongoing trials are testing combinations of lenalidomide with other active anti-myeloma agents such as bortezomib (VELCADE®). In addition to myeloma, lenalidomide has also shown efficacy in a certain form of myelodysplastic syndrome, another disease involving the bone marrow.

Source: http://myeloma.org/main.jsp?type=article&id=1576

FDA reviews Revlimid for Multiple Myeloma

FDA Grants Priority Review for REVLIMID(R) sNDA for Treatment of Relapsed or Refractory Multiple Myeloma

June 30, 2006 PDUFA Date Established Expanded Access Program to Remain Open Through FDA Action on REVLIMID sNDA

Celgene Corporation announced that the U.S. Food and Drug Administration (FDA) has granted a Priority Review designation to its Supplemental New Drug Application (sNDA) for REVLIMID (lenalidomide) for the treatment of relapsed or refractory multiple myeloma. The Prescription Drug User Fee Act (PDUFA) date is June 30, 2006. The Company is seeking approval to market REVLIMID in combination with dexamethasone as a proposed indication for the treatment of multiple myeloma patients who have received at least one prior therapy subject to FDA review and approval. Priority Review is granted to a pharmaceutical product that, if approved, would be a significant improvement compared to existing marketed products or approved therapies in the treatment, diagnosis, or prevention of a disease.

The REVLIMID sNDA submission is based upon the safety and efficacy results of two large randomized pivotal Phase III special protocol assessment trials, North American Trial MM-009 and International Trial MM-010, evaluating REVLIMID plus dexamethasone in multiple myeloma patients that have received at least one prior therapy. Based on a pre-specified interim analysis, both studies achieved the primary endpoint of time to disease progression (TTP) with combination therapy of lenalidomide and dexamethasone over that of placebo and dexamethasone. The clinical data, both from MM-009 and MM-010, were presented during a plenary session at the December 2005 meeting of the American Society of Hematology (ASH).

The Celgene Expanded Access Program, available to qualified patients with relapsed or refractory multiple myeloma, will remain open to ensure broad access to REVLIMID while the REVLIMID sNDA is under review by the FDA.

SAFETY NOTICE:

REVLIMID(R) (lenalidomide) Capsules 5 mg & 10 mg

WARNINGS:

1. POTENTIAL FOR HUMAN BIRTH DEFECTS.

LENALIDOMIDE IS AN ANALOGUE OF THALIDOMIDE. THALIDOMIDE IS A KNOWN HUMAN TERATOGEN THAT CAUSES SEVERE LIFE-THREATENING HUMAN BIRTH DEFECTS. IF LENALIDOMIDE IS TAKEN DURING PREGNANCY, IT MAY CAUSE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY. FEMALES SHOULD BE ADVISED TO AVOID PREGNANCY WHILE TAKING REVLIMID(R) (lenalidomide).

Special Prescribing Requirements

BECAUSE OF THIS POTENTIAL TOXICITY AND TO AVOID FETAL EXPOSURE TO REVLIMID(R) (lenalidomide), REVLIMID(R) (lenalidomide) IS ONLY AVAILABLE UNDER A SPECIAL RESTRICTED DISTRIBUTION PROGRAM. THIS PROGRAM IS CALLED "RevAssist(SM)." UNDER THIS PROGRAM, ONLY PRESCRIBERS AND PHARMACISTS REGISTERED WITH THE PROGRAM ARE ABLE TO PRESCRIBE AND DISPENSE THE PRODUCT. IN ADDITION, REVLIMID(R) (lenalidomide) MUST ONLY BE DISPENSED TO PATIENTS WHO ARE REGISTERED AND MEET ALL THE CONDITIONS OF THE RevAssist(SM) PROGRAM.

WARNINGS:

2. HEMATOLOGICAL TOXICITY

(NEUTROPENIA AND THROMBOCYTOPENIA)

REVLIMID(R) (lenalidomide) IS ASSOCIATED WITH SIGNIFICANT NEUTROPENIA AND THROMBOCYTOPENIA. PATIENTS SHOULD HAVE THEIR CBC CHECKED WEEKLY FOR THE FIRST 8 WEEKS OF REVLIMID(R) (lenalidomide) TREATMENT AND AT LEAST MONTHLY THEREAFTER TO MONITOR FOR CYTOPENIAS. MOST DELETION 5q MDS PATIENTS STUDIED REQUIRED A DOSE ADJUSTMENT FOR NEUTROPENIA AND/OR THROMBOCYTOPENIA.

3. DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM

REVLIMID(R) (lenalidomide) HAS DEMONSTRATED SIGNIFICANT RISK OF DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM IN SOME PATIENTS WITH CERTAIN MEDICAL CONDITIONS.

IMPORTANT SAFETY INFORMATION

Hypersensitivity: REVLIMID(R) (lenalidomide) is contraindicated in any patients who have demonstrated hypersensitivity to the drug or its components.

Other adverse events: Other most frequently reported adverse events were diarrhea, pruritis, rash, fatigue, constipation, nausea, nasopharyngitis, arthralgia, pyrexia, back pain, peripheral edema, cough, dizziness, headache, muscle cramp, dyspnea, and pharyngitis. REVLIMID(R) (lenalidomide) is substantially excreted by the kidney, so the risk of toxic reactions may be greater in patients with impaired renal function.

About REVLIMID(R)

REVLIMID is a member of a proprietary group of novel immunomodulatory compounds, IMiDs(R). Celgene continues to evaluate REVLIMID in a broad range of hematology and oncology conditions. The IMiD pipeline, including REVLIMID, is covered by a comprehensive intellectual property estate of U.S. and foreign issued and pending patent applications including composition-of-matter and use patents.

REVLIMID is approved by the FDA for treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. REVLIMID is not approved by the FDA or any other regulatory agencies as a treatment for any other indication and is currently being evaluated in clinical trials for efficacy and safety for future regulatory applications.

About RevAssist(SM)

FOR FURTHER INFORMATION ABOUT REVLIMID(R) AND THE RevAssist(SM) PROGRAM, YOU MAY GO TO THE INTERNET AT www.REVLIMID.com OR BY CALLING THE MANUFACTURER'S TOLL FREE NUMBER 1-888-4CELGENE. RevAssist(SM) is a proprietary risk-management restrictive distribution program, tailored specifically for REVLIMID patients, to prevent the potential for human birth defects and ensure prompt and convenient access to REVLIMID.

SOURCE Celgene Corporation Press Release at http://www.celgene.com

Therapy: LD-VTD

Low dose Velcade, thalidomide and dexamethasone (LD-VTD): an effective regimen for relapsed and refractory multiple myeloma patients.

Ciolli S, Leoni F, Gigli F, Rigacci L, Bosi A.

From January 2004, R/R MM cases referred to the Institution received LD-VTD regimen. Patients, irrespective of age, PS and life expectancy, were enrolled in the study once they had a measurable disease. Planned therapy: Velcade 1.0 mg m(-2) i.v. twice weekly for 2 weeks of a 28-day cycle for up to 6 cycles, oral Dexamethasone 24 mg on the day of and the day following each Velcade dose and Thalidomide 100 mg each evening. DVT prophylaxis with warfarin to maintain international normalized ratio between 2.0-3.0 was planned in all patients. As of 1 June 2005, 18 were the treated patients: median age 63 years, median time from diagnosis 5.8 years, a median of 4 previous therapy lines. Seventeen were the valuable patients and 9 (53%) were the responders: 2 CR, 6 PR, 1 MR. Six were the stable disease and 2 the progressive ones. Median time to best response was 2 months. Toxicity was negligible. No case of DVT was recorded. Except for the first cycle, subsequent cycles were delivered on an outpatient basis. After a median follow-up of 11 months, 12 patients were alive and 5 died (3 disease progression, 1 heart failure, 1 intestinal bleeding). Thus, the LD-VTD regimen applied appears feasible and effective in elderly and heavily pre-treated R/R myeloma patients.

NPI-0052 - The next Velcade?

A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib.

Chauhan D, Catley L, Li G, Podar K, Hideshima T, Velankar M, Mitsiades C, Mitsiades N, Yasui H, Letai A, Ovaa H, Berkers C, Nicholson B, Chao TH, Neuteboom ST, Richardson P, Palladino MA, Anderson KC.

The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.

Bortezomib therapy has proven successful for the treatment of relapsed and/or refractory multiple myeloma (MM); however, prolonged treatment is associated with toxicity and development of drug resistance. Here, we show that the novel proteasome inhibitor NPI-0052 induces apoptosis in MM cells resistant to conventional and Bortezomib therapies. NPI-0052 is distinct from Bortezomib in its chemical structure, effects on proteasome activities, mechanisms of action, and toxicity profile against normal cells. Moreover, NPI-0052 is orally bioactive. In animal tumor model studies, NPI-0052 is well tolerated and prolongs survival, with significantly reduced tumor recurrence. Combining NPI-0052 and Bortezomib induces synergistic anti-MM activity. Our study therefore provides the rationale for clinical protocols evaluating NPI-0052, alone and together with Bortezomib, to improve patient outcome in MM.

PMID: 16286248 [PubMed - indexed for MEDLINE]

Osteonecrosis of the Jaw

Osteonecrosis of the Jaw in Multiple Myeloma Patients: Clinical Features and Risk Factors

Ashraf Badros, Dianna Weikel, Andrew Salama, Olga Goloubeva, Abraham Schneider, Aaron Rapoport, Robert Fenton, Natalie Gahres, Edward Sausville, Robert Ord, Timothy Meiller

From the University of Maryland Marlene and Stewart Greenebaum Cancer Center; University of Maryland Dental School, Baltimore, MD

PURPOSE: To describe the clinical, radiologic, and pathologic features and risk factors for osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients.

PATIENTS AND METHODS: A retrospective review of 90 MM patients who had dental assessments, including 22 patients with ONJ. There were 62 men; the median age was 61 years in ONJ patients and 58 years among the rest. Prior MM therapy included thalidomide (n = 67) and stem-cell transplantation (n = 72). Bisphosphonate therapy included zoledronate (n = 34) or pamidronate (n = 17) and pamidronate followed by zoledronate (n = 33). Twenty-seven patients had recent dental extraction, including 12 patients in the ONJ group. Median time from MM diagnosis to ONJ was 8.4 years for the whole group.

RESULTS: Patients usually presented with pain. ONJ occurred posterior to the cuspids (n = 20) mostly in the mandible. Debridement and sequestrectomy with primary closure were performed in 14 patients; of these, four patients had major infections and four patients had recurrent ONJ. Bone histology revealed necrosis and osteomyelitis. Microbiology showed actinomycetes (n = 7) and mixed bacteria (n = 9). More than a third of ONJ patients also suffered from long bone fractures (n = 4) and/or avascular necrosis of the hip (n = 4). The variables predictive of developing ONJ were dental extraction (P = .009), treatment with pamidronate/zoledronate (P = .009), longer follow-up time (P = .03), and older age at diagnosis of MM (P = .006).

CONCLUSION: ONJ appears to be time-dependent with higher risk after long-term use of bisphosphonates in older MM patients often after dental extractions. No satisfactory therapy is currently available. Trials addressing the benefits/risks of continuing bisphosphonate therapy are needed.

Journal of Clinical Oncology, Vol 24, No 6 (February 20), 2006: pp. 945-952
© 2006 American Society of Clinical Oncology
DOI: 10.1200/JCO.2005.04.2465

Research: ULBP2

A novel bispecific protein (ULBP2-BB4) targeting the NKG2D receptor on natural killer (NK) cells and CD138 activates NK cells and has potent antitumor activity against human multiple myeloma in vitro and in vivo

Elke Pogge von Strandmann, Hinrich P. Hansen, Katrin S. Reiners, Roland Schnell, Peter Borchmann, Sabine Merkert, Venkateswara R. Simhadri, Andreas Draube, Marcel Reiser, Ingvill Purr, Michael Hallek, and Andreas Engert

From the Laboratory of Immunotherapy, Department I for Internal Medicine, University Hospital Cologne, Germany.

The inability of the immune system to recognize and kill malignant plasma cells in patients with multiple myeloma (MM) has been attributed in part to the ineffective activation of natural killer (NK) cells. In order to activate and target NK cells to the malignant cells in MM we designed a novel recombinant bispecific protein (ULBP2-BB4). While ULBP2 binds the activating NK receptor NKG2D, the BB4 moiety binds to CD138, which is overexpressed on a variety of malignancies, including MM. ULBP2-BB4 strongly activated primary NK cells as demonstrated by a significant increase in interferon- (IFN-) secretion. In vitro, ULBP2-BB4 enhanced the NK-mediated lysis of 2 CD138⁺ human MM cell lines, U-266 and RPMI-8226, and of primary malignant plasma cells in the allogenic and autologous setting. Moreover, in a nude mouse model with subcutaneously growing RPMI-8226 cells, the cotherapy with ULBP-BB4 and human peripheral blood lymphocytes abrogated the tumor growth. These data suggest potential clinical use of this novel construct in patients with MM. The use of recombinant NK receptor ligands that target NK cells to tumor cells might offer new approaches for other malignancies provided a tumor antigen-specific antibody is available.